Glucagon-like-peptide-1 (referred to hereinafter as GLP-1) is a proglucagon-derived peptide secreted from intestinal L-cells in response to nutrient ingestion (Drucker, D J: The Glucagon-Like Peptides. Diabetes 47:159-169, 1998). GLP-1 acts as an incretin to stimulate the release of insulin from pancreatic beta cells in conjunction with carbohydrates that are absorbed from the gut. GLP-1 also exerts actions independent of islet hormone secretion, including inhibition of both gastric emptying and food intake and stimulation of β-cell proliferation.
Significantly, GLP-1 possesses the ability to rapidly lower glucose levels in both normal and diabetic subjects (Gutniak, M., et al., N Engl J Med 326:1316-1322, 1992; Nauck M A, et al., J Clin Invest 91:301-307, 1993). In a six-week study in humans, continuous subcutaneous infusion of native GLP-1 significantly decreased blood glucose and HbA1c in patients with type 2 diabetes (Zander M, et al., Lancet 359:824-830, 2002). Based on results such as these, there has been considerable interest in developing GLP-1 based pharmaceutical agents for the treatment of type-2 diabetes and the like.
Although native GLP-1 effectively lowers blood glucose following administration, its usefulness as a therapeutic agent is severely hampered due to the fact that native GLP-1 (amino acids 1-37) is poorly active, and its two naturally-occurring truncated versions, GLP-1 (7-37) and GLP-1 (7-36)NH2, have extremely short in vivo half-lives. The short in vivo half-life of GLP-1 is due primarily to NH2-terminal cleavage and inactivation by the enzyme, dipeptidyl peptidase, DPP-IV (Kieffer T J et al., Endocrinology 136:3585-3596, 1995).
Various approaches have been explored to attempt to circumvent the rapid in vivo cleavage of GLP-1 by DPP-IV. For example, GLP-1 analogs having one or more amino acid substitutions aimed at reducing the affinity of GLP-1 for DPP-IV to attenuate its cleavage have been prepared (Drucker D J, Curr Pharm Des 7:1399-1412, 2001; Drucker D J, Gastroenterology 122:531-544, 2002). Similarly, the naturally-occurring lizard peptide, exendin-4, has been found to be a potent GLP-1R agonist that exhibits reduced DPP-IV mediated cleavage and possesses a longer duration of action than GLP-1 (Young, A A, et al., Diabetes 48:1026-1034, 1999; Edwards C M, et al., Am J Physiol Endicrinol Metab 281:E155-161, 2001). GLP-1 derivatives having a short covalent chemical linker designed to interact with a specific cysteine residue in albumin following administration have also been developed (Kim, J G, et al., Diabetes 52, 751, 2003), as have GLP-1 analogs having several modifications including a modified N-terminus, an octanoic acid acylated at lysine-34, and a substitution of arginine at position 26 (Chou, J., et al., J. Pharm Sci, 86 (7), 768-773, 2000). Additionally, stable covalent attachment of polyethylene glycol to GLP-1 has been described (See, e.g., WO 2004/093823).
While these and other various approaches appear to describe GLP-1 compounds having improved therapeutic properties when compared to native GLP-1, there still exists a need for improved GLP-1 compounds capable of providing additional therapeutic advantages over existing GLP-1 based therapeutic agents. Thus, there remains a need in the art to provide additional advantageous GLP-1 moiety-polymer conjugates. Among other things, one or more embodiments of the present invention are therefore directed to such conjugates as well as compositions comprising the conjugates and related methods as described herein.